title: Life-stage-, sex-, and dose-dependent dietary toxicokinetics and relationship to toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats: implications for toxicity test dose selection, design, and interpretation.
abstract: Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥ 1200 ppm (63 mg/kg/day) for P1 males and between 200 and 400 ppm (14-27 mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21-35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies.
authors.affiliation: * Intrinsik Environmental Sciences Inc., Mississauga, Ontario, Canada L5T 0A3, and Aga Khan University, Karachi, Pakistan 74800;
authors.forename: Shakil A
authors.initials: SA
authors.lastname: Saghir
authors.forename: Mary S
authors.initials: MS
authors.lastname: Marty
authors.forename: Carol L
authors.initials: CL
authors.lastname: Zablotny
authors.forename: Julie K
authors.initials: JK
authors.lastname: Passage
authors.forename: Adam W
authors.initials: AW
authors.lastname: Perala
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Neal
authors.forename: Larry
authors.initials: L
authors.lastname: Hammond
authors.forename: James S
authors.initials: JS
authors.lastname: Bus
mesh_terms: D015084:2,4-Dichlorophenoxyacetic Acid / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D018675:Toxicity Tests
chemical_list: D015084:2,4-Dichlorophenoxyacetic Acid
keywords: 2,4-D; 2,4-dichlorophenoxyacetic acid; PK; TK; development; perinatal; pharmacokinetics; rats.; toxicity; toxicokinetics